Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) are the currently recommended first- and second-line therapies for uncomplicated Plasmodium falciparum infections in Togo. This study assessed the efficacy of these combinations, the proportion of Day3-positive patients (D3 +), the proportion of molecular markers associated with P. falciparum resistance to anti-malarial drugs, and the variable performance of HRP2-based malaria rapid diagnostic tests (RDTs). A single arm prospective study evaluating the efficacy of AL and DP was conducted at two sites (Kouvé and Anié) from September 2021 to January 2022. Eligible children were enrolled, randomly assigned to treatment at each site and followed up for 42 days after treatment initiation. The primary endpoint was polymerase chain reaction (PCR) adjusted adequate clinical and parasitological response (ACPR). At day 0, samples were analysed for mutations in the Pfkelch13, Pfcrt, Pfmdr-1, dhfr, dhps, and deletions in the hrp2/hrp3 genes. A total of 179 and 178 children were included in the AL and DP groups, respectively. After PCR correction, cure rates of patients treated with AL were 97.5% (91.4–99.7) at day 28 in Kouvé and 98.6% (92.4–100) in Anié, whereas 96.4% (CI 95%: 89.1–98.8) and 97.3% (CI 95%: 89.5–99.3) were observed at day 42 in Kouvé and Anié, respectively. The cure rates of patients treated with DP at day 42 were 98.9% (CI 95%: 92.1–99.8) in Kouvé and 100% in Anié. The proportion of patients with parasites on day 3 (D3 +) was 8.5% in AL and 2.6% in DP groups in Anié and 4.3% in AL and 2.1% DP groups in Kouvé. Of the 357 day 0 samples, 99.2% carried the Pfkelch13 wild-type allele. Two isolates carried nonsynonymous mutations not known to be associated with artemisinin partial resistance (ART-R) (A578S and A557S). Most samples carried the Pfcrt wild-type allele (97.2%). The most common Pfmdr-1 allele was the single mutant 184F (75.6%). Among dhfr/dhps mutations, the quintuple mutant haplotype N51I/C59R/S108N + 437G/540E, which is responsible for SP treatment failure in adults and children, was not detected. Single deletions in hrp2 and hrp3 genes were detected in 1/357 (0.3%) and 1/357 (0.3%), respectively. Dual hrp2/hrp3 deletions, which could affect the performances of HRP2-based RDTs, were not observed. The results of this study confirm that the AL and DP treatments are highly effective. The absence of the validated Pfkelch13 mutants in the study areas suggests the absence of ART -R, although a significant proportion of D3 + cases were found. The absence of dhfr/dhps quintuple or sextuple mutants (quintuple + 581G) supports the continued use of SP for IPTp during pregnancy and in combination with amodiaquine for seasonal malaria chemoprevention. Trial registration: ACTRN12623000344695.

中文翻译：

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2021年多哥儿童蒿甲醚-本芴醇和双氢青蒿素-哌喹的疗效及抗疟疾耐药分子标志物流行情况

蒿甲醚-本芴醇 (AL) 和双氢青蒿素-哌喹 (DP) 是目前在多哥推荐的治疗单纯性恶性疟原虫感染的一线和二线疗法。这项研究评估了这些组合的功效、第 3 天阳性患者 (D3+) 的比例、与恶性疟原虫对抗疟疾药物耐药性相关的分子标志物的比例，以及基于 HRP2 的疟疾快速诊断测试的可变性能（RDT）。 2021 年 9 月至 2022 年 1 月在两个地点（Kouvé 和 Anié）进行了一项评估 AL 和 DP 疗效的单臂前瞻性研究。招募符合条件的儿童，随机分配到每个地点接受治疗，并在治疗开始后随访 42 天。主要终点是聚合酶链反应（PCR）调整足够的临床和寄生虫学反应（ACPR）。第 0 天，分析样本中 Pfkelch13、Pfcrt、Pfmdr-1、dhfr、dhps 的突变以及 hrp2/hrp3 基因的缺失。 AL 组和 DP 组分别包括 179 名和 178 名儿童。 PCR 校正后，第 28 天时，Kouvé 和 Anié 的 AL 治疗患者治愈率为 97.5% (91.4–99.7) 和 98.6% (92.4–100)，而 AL 治疗患者的治愈率为 96.4% (CI 95%: 89.1–98.8) 和 97.3% （CI 95%：89.5–99.3）分别在第 42 天在 Kouvé 和 Anié 中观察到。第 42 天接受 DP 治疗的患者的治愈率在 Kouvé 中为 98.9%（CI 95%：92.1–99.8），在 Anié 中为 100%。在阿尼埃，第 3 天（D3+）有寄生虫的患者比例在 AL 组中为 8.5%，在 DP 组中为 2.6%；在 Kouvé 中，AL 组和 DP 组中为 4.3%，为 2.1%。在 357 个第 0 天样本中，99.2% 携带 Pfkelch13 野生型等位基因。两个分离株携带未知与青蒿素部分耐药性 (ART-R)（A578S 和 A557S）相关的非同义突变。大多数样本携带 Pfcrt 野生型等位基因 (97.2%)。最常见的 Pfmdr-1 等位基因是单一突变体 184F (75.6%)。在dhfr/dhps突变中，未检测到导致成人和儿童SP治疗失败的五重突变单倍型N51I/C59R/S108N + 437G/540E。检测到 hrp2 和 hrp3 基因的单个缺失的比例分别为 1/357 (0.3%) 和 1/357 (0.3%)。没有观察到可能影响基于 HRP2 的 RDT 性能的双 hrp2/hrp3 缺失。本研究结果证实 AL 和 DP 治疗非常有效。尽管发现了很大比例的 D3 + 病例，但研究区域中缺乏经过验证的 Pfkelch13 突变体表明不存在 ART -R。 dhfr/dhps 五重或六重突变体（五重 + 581G）的缺失支持在怀孕期间继续使用 SP 进行 IPTp 以及与阿莫地喹联合用于季节性疟疾化学预防。试用注册：ACTRN12623000344695。